tbuckley/cabot-search huggingface dataset:
Abstract 2464: Novel models of breast cancer metastasis with different metastatic competence
Authors: Akshita B. Bhatt, Ruishan Wang, Hong Jia, Myriam Labelle
Journal: Cancer Research (2023)

Abstract Metastasis is responsible for poor overall survival of cancer patients and a better understanding of the molecular mechanisms that drive metastasis is crucial for improving disease outcome. In mouse models, gene expression profiling of cancer cells isolated from metastases and from their matched primary tumors is an approach that has been successfully employed to identify biomarkers and drivers of metastasis. However, only few such tumor pairs have been derived from immunocompetent mouse models, limiting our ability to compare the metastatic potentials of these pairs in the context of an intact immune system. Moreover, most of the metastatic cancer cell lines currently available on the C57BL/6 background have a relatively low metastatic potential, complicating the evaluation of therapeutic interventions that may inhibit metastasis. To address these critical limitations, we developed novel cell lines from distinct spontaneous lung metastases and corresponding primary breast tumors from C57BL/6 mice. Specifically, C57BL/6 mice were orthotopically injected with copGFP-expressing E0771 breast cancer cells and the tumors were allowed to grow for 28 days. Tumor cells at different stages of the metastatic cascade - primary tumor evolution, transit through the blood circulation (circulating tumor cells), survival at secondary site, dormancy, and metastatic outgrowth, were captured by collecting and culturing copGFP-positive cancer cell lines from the primary tumor, blood circulation, and metastatic lungs at the experimental endpoint. These cells were reintroduced orthotopically (mammary fat pad injection) and intravenously (tail-vein injection) to evaluate tumor growth and metastasis in vivo. Interestingly, cell lines derived from overt metastases displayed a wide array of metastatic competences, indicating that some metastases retain that ability to further metastasize while others do not. RNA sequencing of these cell lines identified genes and pathways that are significantly upregulated in highly metastatic vs. poorly metastatic cancer cell lines. Future studies will investigate whether modulation of these pathways in the primary tumor and CTCs can be used to predict metastatic recurrence and serve as a basis for developing novel biomarker-based therapeutic approaches for the treatment of metastatic disease. We also envision that the cell lines we generated will be useful for studies of the influence of host-tumor cells interactions on metastasis on the immunocompetent C57BL/6 background. Citation Format: Akshita B. Bhatt, Ruishan Wang, Hong Jia, Myriam Labelle. Novel models of breast cancer metastasis with different metastatic competence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2464.
Abstract 2468: Overcoming the leptomeningeal seeding of medulloblastoma by targeting HSP70
Authors: Seung Ah Choi, Saehim Ha, Hee-Young Lee, Joo Whan Kim, Jin Chul Paeng, Ji Hoon Phi
Journal: Cancer Research (2023)

Abstract Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor and the development of leptomeningeal dissemination (LM seeding) through the cerebrospinal fluid (CSF) circulation is a major cause of treatment failure. We have previously established the MB LM seeding mouse model. In this study, we aimed to determine molecules that can target seeding (metastatic) cells by analyzing their specific genetic and functional characteristics. Methods: Seeding and non-seeding cells were isolated and cultured, respectively, and microarray analysis was carried out. Proliferation and wound-healing assays were performed through the HCS system, and viability, migration and adhesion assays were accomplished. In addition, the therapeutic effect of the selected inhibitor was analyzed by region of interest (ROI) analysis of bioluminescence in vivo. Results: The gene expression and functional characteristics of the successfully obtained seed cells and non-seed cells were compared and analyzed. Differentially expressed genes (DEGs) analysis indicated that heat shock protein 70 (Hsp70) was in the highest rank in seeding cells, and pathway enrichment analysis revealed that the metabolism was the main pathway enriched in seeding cells. Proliferation of seeding cells was slower than that of non-seeding cells, but there was no significant difference in viability. Notably, the wound-healing of seeding cells was delayed, but the adhesion ability on collagen was higher. Among the six HSP70 inhibitors, VER155008 was efficiently sensitive to seeding cells, and suppression of expression of MRP proteins along with HSP70 was also confirmed. In addition, it was observed that the treatment of VER155008 reduced seeding through the spinal cord in vivo. Conclusion: Our study suggests that VER15008 can be a promising treatment option, targeting LM seeding of MB. Citation Format: Seung Ah Choi, Saehim Ha, Hee-Young Lee, Joo Whan Kim, Jin Chul Paeng, Ji Hoon Phi. Overcoming the leptomeningeal seeding of medulloblastoma by targeting HSP70 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2468.
Abstract 20: <i>In vitro</i> and i<i>n vivo</i> investigation of tumor treating fields for treatment of spinal metastasis
Authors: Claudio Esteves Tatsui, Daniel Ledbetter, Christopher Alvarez-Breckenridge
Journal: Cancer Research (2023)

Abstract Introduction: Tumor treating fields (TTF) are used for treatment of glioblastoma. Its utilization for spinal metastasis has never been described. We investigate the anti-mitotic effect of TTF to inhibit the growth of human cancer cells in vitro and in vivo models of spinal metastasis. Methods: In vitro: human derived osteosarcoma (Krib-luc-1) and lung adenocarcinoma (A549-luc) cells were seeded in 5 × 3mm human demineralized bone grafts kept in culture while treated with 0kHz (control) or 150kHZ of TTF for 14 days. Bioluminescence images (BLI) were obtained at baseline and 14 days. In vivo: Krib-Luc-1 cells were surgically implanted via transperitoneal approach to L3 vertebra in nude mice. Animals were treated with 0kHz or 150kHz for 30 days or until death. BLI were obtained at day 0 and every 7 days. MRI was obtained at day 22. Histological analysis was performed at the end of the experiment. Control and TTF-treated groups were compared with two-tailed t-tests. Results: In vitro: BLI of the control groups demonstrated 5-fold and 34-fold higher tumor signal (photons/sec) than corresponding 150 kHz TTF treatment groups at 14 days (A549 p=0.0289; KRIB p=0.00895). In vivo: All mice receiving 0 kHz treatment displayed hind limb paralysis by day 30, while mice treated with 150 kHz TTF displayed tail drop or no signs of paralysis. MRI and histology confirmed smaller tumors corroborating to BLI (3.67-fold change in photons/sec) (p=0.0212) when the 150 kHz TTF treatment group was compared to controls. Conclusions: Application of TTF at 150kHz reduced cellular proliferation in both in vitro and in vivo models of spinal metastasis. This is the first report of utilization of TTF for treatment of bony tumors and represents the first evidence that TTF could become a revolutionary therapy for spinal metastasis. Citation Format: Claudio Esteves Tatsui, Daniel Ledbetter, Christopher Alvarez-Breckenridge. In vitro and in vivo investigation of tumor treating fields for treatment of spinal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 20.
Abstract 4214: Exposure to air pollution during pregnancy and risk of premenopausal breast cancer: A Swedish nation-wide cohort study including more than 1 million women
Authors: Jessica Lena Edlund, Malin Gustafsson, Jenny Linden, Wendy Yi-Ying Wu, Anna Oudin, Sophia Harlid
Journal: Cancer Research (2023)

Abstract Background: Air pollution has been linked to an increased risk of breast cancer, but most previous studies have not considered if the exposure occurred during windows of susceptibility, such as pregnancy. Pregnancy is a period of rapid changes to both the breast tissue and the surrounding microenvironment. Exposures during this sensitive time-period could therefore result in erosion of the protective effect of pregnancy and make women more susceptible to external breast cancer risk factors. Aim: The aim of this study was to identify associations between air pollution exposure, occurring specifically during pregnancy, and risk of premenopausal breast cancer. Method: Using nation-wide data from Swedish registers we constructed a cohort consisting of all women in Sweden who gave birth to their first child between January 1st 1991 and December 31st 2015. Women with a cancer diagnosis prior to pregnancy were excluded. Data on air pollution (yearly averages of PM10, PM2.5 and NO2), was collected from the residence of women during, and to some extent between, pregnancies. Associations between air pollution and premenopausal breast cancer is evaluated using Cox proportional hazards regression to estimate hazard ratios (HR), using age as the time scale and including appropriate confounders such as socioeconomic variables, comorbidities and family history of breast or ovarian cancer. Results: The full cohort included 1 074 925 unique women and 2 302 256 pregnancies (the mean number of pregnancies for each woman was 1.75). During the study period, 13 292 (1.2 %) were diagnosed with breast cancer before they turned 50 years. Conclusion: Our working hypothesis is that women exposed to higher levels of air pollution during pregnancy will have a higher risk of breast cancer. This large-scale study will have enough statistical power to detect the effect of air pollution on breast cancer risk, taking into account exposure both during and between pregnancies. Citation Format: Jessica Lena Edlund, Malin Gustafsson, Jenny Linden, Wendy Yi-Ying Wu, Anna Oudin, Sophia Harlid. Exposure to air pollution during pregnancy and risk of premenopausal breast cancer: A Swedish nation-wide cohort study including more than 1 million women. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4214.
Abstract 3392: Antitumor activity of a potent MNK inhibitor NSP-1047 in acute myeloid leukemia
Authors: Bing Li, Qionglin Huang, Ke Zhang, Jianming Zhang
Journal: Cancer Research (2023)

Abstract MAPK-interacting kinases (MNKs) phosphorylate the eukaryotic initiation factor 4E (eIF4E) and promote the synthesis of tumorigenic proteins. MAPK/MNK/eIF4E pathway is activated in many kinds of haematological and solid tumors. Here, we report the discovery of a novel polycyclic compound NSP-1047, which potently inhibits MNK1 and MNK2, and has sub-nanomolar cellular potency inhibiting phosphorylation of eIF4E. NSP-1047 potently inhibits the expression of multiple immune checkpoint proteins, including PD-1, Tim-3, and Lag-3, and it also inhibits the secretion of several inflammatory cytokines, such as IL-6, IL-8 and IL-10. NSP-1047 displays excellent ADME and pharmacokinetic properties, and demonstrates potent in vivo antitumor activity in acute myeloid leukemia animal models with tumor regression. Citation Format: Bing Li, Qionglin Huang, Ke Zhang, Jianming Zhang. Antitumor activity of a potent MNK inhibitor NSP-1047 in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3392.
Abstract 2457: Restoring the balance between WNT and retinoic acid signaling to promote differentiation of cancer stem cells in treatment of colorectal cancer
Authors: Caroline O. B. Facey, Victoria O. Hunsu, Brian T. Osmond, Chi Zhang, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2023)

Abstract Dysregulated WNT signaling caused by mutation in the APC gene occurs in 80-90% of all colorectal cancer (CRC) cases. Progressive overpopulation of ALDH+ stem cells occurs during development of CRC in familial adenomatous polyposis (FAP) patients. Given that ALDH is a key member of the retinoic acid signaling (RA) pathway, we hypothesize that human CRC is caused by an imbalance between dysregulated WNT and RA signaling. Herein, we aim to restore proper WNT and RA signaling and identify a common link or target to induce differentiation of CSCs along the neuroendocrine cell (NEC) lineage. Accordingly, to determine the effects of restoring wt-APC in APC-mutant HT29 CRC cells, we conducted in vitro experiments to examine Wnt/β-catenin signaling, sensitivity to retinoids, cell proliferation, expression of stem cell markers, quantification of ALDH+ stem cells, and NEC maturation. We utilized Nanostring profiling, TCF reporter assay, western blot, and fluorescence activated cell sorting analyses to ascertain these effects. We found that induction of wt-APC expression decreased WNT/β-catenin signaling and reduced protein expression of WNT-target genes. Notably, inducing wt-APC decreased ATRA-induced expression of the WNT target gene CYP26A1 (by 50%), which is predicted to, in turn, increase RA signaling by lowering degradation of RA. Indeed, inducing wt-APC increased sensitivity of CRC cells to ATRA-induced apoptosis and inhibition of cell proliferation in a dose-dependent manner. Expression of ALDH1A1 decreased (3-fold) with ATRA treatment and inducing wt-APC extended the decrease by an additional 2-fold. Furthermore, upon inducing wt-APC, we found an increase in the protein expression of several NEC markers including CHGA, GLP2R, NSE (ENO2), and SSTR1, and an increased number of GLP2R+ NECs. We also discovered a very highly regulated protein network of 248 proteins and identified a cell signaling mechanism that links the WNT and retinoic acid pathways via CYP26A1. Thus, by inducing wt-APC expression and exogenously activating RA signaling, we found a way to increase differentiation of SCs along the NEC (and other) lineage(s). Translating this strategy in vivo might lead to new, more effective treatments involving retinoids for CRC patients. Citation Format: Caroline O. B. Facey, Victoria O. Hunsu, Brian T. Osmond, Chi Zhang, Lynn M. Opdenaker, Bruce M. Boman. Restoring the balance between WNT and retinoic acid signaling to promote differentiation of cancer stem cells in treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2457.
Abstract 279: Lysosomal cyst(e)ine regulates melanoma de-differentiation and sensitivity to ferroptosis
Authors: Deyang Yu, Jiaxin Liang, Hans Widlund, Pere Puigserver
Journal: Cancer Research (2023)

Abstract In response to anti-melanoma treatment, melanoma cells go through a process called de-differentiation that is characterized as loss of cellular features of melanocytes and acquisition of traits of the primitive neural crest stem cells which give rise to melanocytes during embryonic development. While de-differentiation enables melanoma to resist anti-melanoma drugs, it also exposes certain vulnerabilities of melanoma. A recent study showed that de-differentiated melanoma cells, while resistant to standard anti-melanoma therapies, display remarkable sensitivity to a group of chemicals that cause a special type of cell death called ferroptosis. However, the cellular programs and molecular machineries that drive melanoma de-differentiation and make them vulnerable to ferroptosis remain unknown. As the master regulator of melanocyte differentiation, MITF is often lost during de-differentiation and this loss has been correlated with sensitivity to ferroptosis. Through proteomic profiling of melanoma cells with different MITF status, we found that MITF-mediated lysosomal biogenesis is a key difference between differentiated melanoma cells and de-differentiated melanoma cells. Importantly, within the same melanoma linage, the heterogeneity in lysosomal abundance underlies differential sensitivity to ferroptosis. To probe lysosomal function that controls ferroptosis sensitivity, we deleted a series of lysosome-related proteins and found that the lysosomal cysteine transporters CTNS and MFSD12 exert opposing effects on lysosomal de-differentiation and ferroptosis sensitivity. Specifically, deletion of the pH-dependent cystine exporter CTNS drives melanoma de-differentiation and promotes ferroptosis sensitivity while ablation of cysteine importer MFSD12 further enhances resistance to ferroptosis. On the other hand, while increasing lysosomal cystine export by overexpression of CTNS has moderate effects on melanoma de-differentiation, increasing lysosomal important by overexpression of MFSD12 results in melanoma de-differentiation and increases sensitivity to ferroptosis. Our findings suggest that disruption of lysosomal cysteine homeostasis is a key mechanism to drive melanoma de-differentiation which is accompanied by increased sensitivity to ferroptosis. Citation Format: Deyang Yu, Jiaxin Liang, Hans Widlund, Pere Puigserver. Lysosomal cyst(e)ine regulates melanoma de-differentiation and sensitivity to ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 279.
Abstract 4962: Discovery of cancer-specific E3 ligase ligands for targeted protein degradation
Authors: Zhaofu Wang, Lynette Zhang, Zhen Chang, Mengxi Zhao, Guobin Li, Fang Qin, Shichao Ma, Yunfeng Li, Zhongguo Zhang, Xinghao Wang, Ying Kong, Shidi Lou, Sheng Chen, Lanzhen Liu, Shuaijie Xu, Hailong Zhang
Journal: Cancer Research (2023)

Abstract F-box/WD repeat-containing protein 7 (FBXW7) is the substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. FBXW7 recognizes and binds phosphor-degrons within target proteins and capture them to SCF complex for ubiquitination. Know FBXW7 substrates include cyclin-E, DISC1, JUN, MYC, NFE2L1, NOTCH2, MCL1, RICTOR, and NOTCH1 released notch intracellular domain (NICD). FBXW7 is frequently mutated in cancer, results in loss of substrate recognition and binding. R465C is a one of the major FBXW7 mutations and is found in over 70,000 cancer patients worldwide. From a high-throughput screen, we discovered compounds that selectively bind to FBXW7 R465C mutant. PROTACs against various protein targets have been made with these mutant specific ligands. Some of these PROTACs could induce targeted protein degradation in cells carrying FBXW7 R465C mutant but not wild-type FBXW7. Targeted protein degradation with these PROTACs could represent a novel therapeutic approach against FBXW7 R465C mutant cancer. Citation Format: Zhaofu Wang, Lynette Zhang, Zhen Chang, Mengxi Zhao, Guobin Li, Fang Qin, Shichao Ma, Yunfeng Li, Zhongguo Zhang, Xinghao Wang, Ying Kong, Shidi Lou, Sheng Chen, Lanzhen Liu, Shuaijie Xu, Hailong Zhang. Discovery of cancer-specific E3 ligase ligands for targeted protein degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4962.
Abstract 6236: Stellettin B induces apoptosis and autophagy in human bladder cancer RT112 cells
Authors: Mei-Chuan Chen, Chun-Han Chang
Journal: Cancer Research (2023)

Abstract Bladder cancer is one of the most prevalent cancers worldwide. Although most of the patients have good prognosis and good life expectancy with standard treatments, recurrence rate and five-year survival rate have not been significantly improved in patients with bladder cancer, demonstrating there is an urgent need for development of a novel therapeutic strategy for the treatment of bladder cancer. Stellettin B (SP-2), a triterpene isolated from marine sponge Jaspis stellifera , suppresses cell viability in bladder cancer RT112 cells without severe toxicity toward normal uroepithelial SV-HUC-1 cells. Our results showed that SP-2 induces accumulation of cells at subG1 phase in parallel with increase of early apoptotic cells via annexin V/PI staining and activation of cell apoptotic death proteins. Moreover, non-cytotoxic concentrations of SP-2 induces LC3-II formation and p62 downregulation to activate autophagy in RT112 cells, suggesting autophagy may play a role in SP-2 -induced cell death. Inhibition of autophagy by pharmacological inhibitors (3-MA and chloroquine) or ATG5 knockout protects stellettin B-induced apoptosis and cell viability suppression, indicating SP-2 induces autophagy to promotes cell death. Taken together, stellettin B may be a promising therapeutic agent for bladder cancer treatment. Citation Format: Mei-Chuan Chen, Chun-Han Chang. Stellettin B induces apoptosis and autophagy in human bladder cancer RT112 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6236.